Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing.

BACKGROUND: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

An ingestible self-propelling device for intestinal reanimation.

Postoperative ileus (POI) is the leading cause of prolonged hospital stay after abdominal surgery and is characterized by a functional paralysis of the digestive tract, leading to symptoms such as constipation, vomiting, and functional obstruction. Current treatments are mainly supportive and inefficacious and yield acute side effects. Although electrical stimulation studies have demonstrated encouraging pacing and entraining of the intestinal slow waves, no devices exist today to enable targeted intestinal reanimation. Here, we developed an ingestible self-propelling device for intestinal reanimation (INSPIRE) capable of restoring peristalsis through luminal electrical stimulation. Optimizing mechanical, material, and electrical design parameters, we validated optimal deployment, intestinal electrical luminal contact, self-propelling capability, safety, and degradation of the device in ex vivo and in vivo swine models. We compared the INSPIRE's effect on motility in models of normal and depressed motility and chemically induced ileus. Intestinal contraction improved by 44% in anesthetized animals and up to 140% in chemically induced ileus cases. In addition, passage time decreased from, on average, 8.6 days in controls to 2.5 days with the INSPIRE device, demonstrating significant improvement in motility. Luminal electrical stimulation of the intestine via the INSPIRE efficaciously restored peristaltic activity. This noninvasive option offers a promising solution for the treatment of ileus and other motility disorders.

A vibrating ingestible bioelectronic stimulator modulates gastric stretch receptors for illusory satiety.

Effective therapies for obesity require invasive surgical and endoscopic interventions or high patient adherence, making it challenging for patients with obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. We designed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill, an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release and yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, P < 0.0001) and minimized the weight gain rate (P < 0.05) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

Location-aware ingestible microdevices for wireless monitoring of gastrointestinal dynamics.

Localization and tracking of ingestible microdevices in the gastrointestinal (GI) tract is valuable for the diagnosis and treatment of GI disorders. Such systems require a large field-of-view of tracking, high spatiotemporal resolution, wirelessly operated microdevices and a non-obstructive field generator that is safe to use in practical settings. However, the capabilities of current systems remain limited. Here, we report three dimensional (3D) localization and tracking of wireless ingestible microdevices in the GI tract of large animals in real time and with millimetre-scale resolution. This is achieved by generating 3D magnetic field gradients in the GI field-of-view using high-efficiency planar electromagnetic coils that encode each spatial point with a distinct magnetic field magnitude. The field magnitude is measured and transmitted by the miniaturized, low-power and wireless microdevices to decode their location as they travel through the GI tract. This system could be useful for quantitative assessment of the GI transit-time, precision targeting of therapeutic interventions and minimally invasive procedures.

A Vibrating Ingestible BioElectronic Stimulator Modulates Gastric Stretch Receptors for Illusory Satiety.

Effective therapies for obesity either require invasive surgical or endoscopic interventions or high patient adherence, making it challenging for the nearly 42% of American adults who suffer from obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. Here we developed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill - an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release as well as yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, p< 0.0001) and minimized the weight gain rate (p< 0.03) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

Adaptive conductive electrotherapeutic scaffolds for enhanced peripheral nerve regeneration and stimulation.

BACKGROUND: While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal. METHODS: We describe the design and validation of a platform technology for nerve regeneration and interfacing: adaptive, conductive, and electrotherapeutic scaffolds (ACESs). ACESs are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open surgical and minimally invasive percutaneous approaches. FINDINGS: In a rodent model of sciatic nerve repair, ACESs significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACESs enabled atraumatic, percutaneous removal of leads at forces significantly lower than controls (p < 0.05). In a porcine model, ultrasound-guided percutaneous placement of leads with an injectable ACES near the femoral and cervical vagus nerves facilitated stimulus conduction at significantly greater lengths than saline controls (p < 0.05). CONCLUSION: Overall, ACESs facilitated lead placement, stabilization, stimulation, and atraumatic removal, enabling therapeutic PNS as demonstrated in small- and large-animal models. FUNDING: This work was supported by K. Lisa Yang Center for Bionics at MIT.

RoboCap: Robotic mucus-clearing capsule for enhanced drug delivery in the gastrointestinal tract.

Oral drug delivery of proteins is limited by the degradative environment of the gastrointestinal tract and poor absorption, requiring parenteral administration of these drugs. Luminal mucus represents the initial steric and dynamic barrier to absorption. To overcome this barrier, we report the development of the RoboCap, an orally ingestible, robotic drug delivery capsule that locally clears the mucus layer, enhances luminal mixing, and topically deposits the drug payload in the small intestine to enhance drug absorption. RoboCap's mucus-clearing and churning movements are facilitated by an internal motor and by surface features that interact with small intestinal plicae circulares, villi, and mucus. Vancomycin (1.4 kilodaltons of glycopeptide) and insulin (5.8 kilodaltons of peptide) delivery mediated by RoboCap resulted in enhanced bioavailability 20- to 40-fold greater in ex vivo and in vivo swine models when compared with standard oral delivery (P < 0.05). Further, insulin delivery via the RoboCap resulted in therapeutic hypoglycemia, supporting its potential to facilitate oral delivery of drugs that are normally precluded by absorption limitations.

Erratum: Publisher Correction: Agonist-antagonist muscle strain in the residual limb preserves motor control and perception after amputation.

[This corrects the article DOI: 10.1038/s43856-022-00162-z.].

Agonist-antagonist muscle strain in the residual limb preserves motor control and perception after amputation.

Background: Elucidating underlying mechanisms in subject-specific motor control and perception after amputation could guide development of advanced surgical and neuroprosthetic technologies. In this study, relationships between preserved agonist-antagonist muscle strain within the residual limb and preserved motor control and perception capacity are investigated. Methods: Fourteen persons with unilateral transtibial amputations spanning a range of ages, etiologies, and surgical procedures underwent evaluations involving free-space mirrored motions of their lower limbs. Research has shown that varied motor control in biologically intact limbs is executed by the activation of muscle synergies. Here, we assess the naturalness of phantom joint motor control postamputation based on extracted muscle synergies and their activation profiles. Muscle synergy extraction, degree of agonist-antagonist muscle strain, and perception capacity are estimated from electromyography, ultrasonography, and goniometry, respectively. Results: Here, we show significant positive correlations (P < 0.005-0.05) between sensorimotor responses and residual limb agonist-antagonist muscle strain. Identified trends indicate that preserving even 20-26% of agonist-antagonist muscle strain within the residuum compared to a biologically intact limb is effective in preserving natural motor control postamputation, though preserving limb perception capacity requires more (61%) agonist-antagonist muscle strain preservation. Conclusions: The results suggest that agonist-antagonist muscle strain is a characteristic, readily ascertainable residual limb structural feature that can help explain variability in amputation outcome, and agonist-antagonist muscle strain preserving surgical amputation strategies are one way to enable more effective and biomimetic sensorimotor control postamputation.

Low-cost gastrointestinal manometry via silicone-liquid-metal pressure transducers resembling a quipu.

The evaluation of the tone and contractile patterns of the gastrointestinal (GI) tract via manometry is essential for the diagnosis of GI motility disorders. However, manometry is expensive and relies on complex and bulky instrumentation. Here we report the development and performance of an inexpensive and easy-to-manufacture catheter-like device for capturing manometric data across the dynamic range observed in the human GI tract. The device, which we designed to resemble the quipu-knotted strings used by Andean civilizations for the capture and transmission of information-consists of knotted piezoresistive pressure sensors made by infusing a liquid metal (eutectic gallium-indium) through thin silicone tubing. By exploring a range of knotting configurations, we identified optimal design schemes that led to sensing performances comparable to those of commercial devices for GI manometry, as we show for the sensing of GI motility in multiple anatomic sites of the GI tract of anaesthetized pigs. Disposable and customizable piezoresistive catheters may broaden the use of GI manometry in low-resource settings.

Pre-emptive Innovation Infrastructure for Medical Emergencies: Accelerating Healthcare Innovation in the Wake of a Global Pandemic.

Healthcare innovation is impeded by high costs, the need for diverse skillsets, and complex regulatory processes. The COVID-19 pandemic exposed critical gaps in the current framework, especially those lying at the boundary between cutting-edge academic research and industry-scale manufacturing and production. While many resource-rich geographies were equipped with the required expertise to solve challenges posed by the pandemic, mechanisms to unite the appropriate institutions and scale up, fund, and mobilize solutions at a time-scale relevant to the emergency were lacking. We characterize the orthogonal spatial and temporal axes that dictate innovation. Improving on their limitations, we propose a "pre-emptive innovation infrastructure" incorporating in-house hospital innovation teams, consortia-based assembly of expertise, and novel funding mechanisms to combat future emergencies. By leveraging the strengths of academic, medical, government, and industrial institutions, this framework could improve ongoing innovation and supercharge the infrastructure for healthcare emergencies.

Neural interfacing architecture enables enhanced motor control and residual limb functionality postamputation.

Despite advancements in prosthetic technologies, patients with amputation today suffer great diminution in mobility and quality of life. We have developed a modified below-knee amputation (BKA) procedure that incorporates agonist-antagonist myoneural interfaces (AMIs), which surgically preserve and couple agonist-antagonist muscle pairs for the subtalar and ankle joints. AMIs are designed to restore physiological neuromuscular dynamics, enable bidirectional neural signaling, and offer greater neuroprosthetic controllability compared to traditional amputation techniques. In this prospective, nonrandomized, unmasked study design, 15 subjects with AMI below-knee amputation (AB) were matched with 7 subjects who underwent a traditional below-knee amputation (TB). AB subjects demonstrated significantly greater control of their residual limb musculature, production of more differentiable efferent control signals, and greater precision of movement compared to TB subjects (P < 0.008). This may be due to the presence of greater proprioceptive inputs facilitated by the significantly higher fascicle strains resulting from coordinated muscle excursion in AB subjects (P < 0.05). AB subjects reported significantly greater phantom range of motion postamputation (AB: 12.47 ± 2.41, TB: 10.14 ± 1.45 degrees) when compared to TB subjects (P < 0.05). Furthermore, AB subjects also reported less pain (12.25 ± 5.37) than TB subjects (17.29 ± 10.22) and a significant reduction when compared to their preoperative baseline (P < 0.05). Compared with traditional amputation, the construction of AMIs during amputation confers the benefits of enhanced physiological neuromuscular dynamics, proprioception, and phantom limb perception. Subjects' activation of the AMIs produces more differentiable electromyography (EMG) for myoelectric prosthesis control and demonstrates more positive clinical outcomes.

Agonist-antagonist myoneural interface amputation preserves proprioceptive sensorimotor neurophysiology in lower limbs.

The brain undergoes marked changes in function and functional connectivity after limb amputation. The agonist-antagonist myoneural interface (AMI) amputation is a procedure that restores physiological agonist-antagonist muscle relationships responsible for proprioceptive sensory feedback to enable greater motor control. We compared results from the functional neuroimaging of individuals (n = 29) with AMI amputation, traditional amputation, and no amputation. Individuals with traditional amputation demonstrated a significant decrease in proprioceptive activity, measured by activation of Brodmann area 3a, whereas functional activation in individuals with AMIs was not significantly different from controls with no amputation (P < 0.05). The degree of proprioceptive activity in the brain strongly correlated with fascicle activity in the peripheral muscles and performance on motor tasks (P < 0.05), supporting the mechanistic basis of the AMI procedure. These results suggest that surgical techniques designed to restore proprioceptive peripheral neuromuscular constructs result in desirable central sensorimotor plasticity.

Electroceuticals in the Gastrointestinal Tract.

The field of electroceuticals has attracted considerable attention over the past few decades as a novel therapeutic modality. The gastrointestinal (GI) tract (GIT) holds significant potential as a target for electroceuticals as the intersection of neural, endocrine, and immune systems. We review recent developments in electrical stimulation of various portions of the GIT (including esophagus, stomach, and small and large intestine) and nerves projecting to the GIT and supportive organs. This has been tested with varying degrees of success for several dysmotility, inflammatory, hormonal, and neurologic disorders. We outline a vision for the future of GI electroceuticals, building on advances in mechanistic understanding of GI physiology coupled with novel ingestible technologies. The next wave of electroceutical therapies will be minimally invasive and more targeted than current approaches, making them an indispensable tool in the clinical armamentarium.

A rapidly deployable individualized system for augmenting ventilator capacity.

Strategies to split ventilators to support multiple patients requiring ventilatory support have been proposed and used in emergency cases in which shortages of ventilators cannot otherwise be remedied by production or procurement strategies. However, the current approaches to ventilator sharing lack the ability to individualize ventilation to each patient, measure pulmonary mechanics, and accommodate rebalancing of the airflow when one patient improves or deteriorates, posing safety concerns to patients. Potential cross-contamination, lack of alarms, insufficient monitoring, and inability to adapt to sudden changes in patient status have prevented widespread acceptance of ventilator sharing. We have developed an individualized system for augmenting ventilator efficacy (iSAVE) as a rapidly deployable platform that uses a single ventilator to simultaneously and more safely support two individuals. The iSAVE enables individual-specific volume and pressure control and the rebalancing of ventilation in response to improvement or deterioration in an individual's respiratory status. The iSAVE incorporates mechanisms to measure pulmonary mechanics, mitigate cross-contamination and backflow, and accommodate sudden flow changes due to individual interdependencies within the respiratory circuit. We demonstrate these capacities through validation using closed- and open-circuit ventilators on linear test lungs. We show that the iSAVE can temporarily ventilate two pigs on one ventilator as efficaciously as each pig on its own ventilator. By leveraging off-the-shelf medical components, the iSAVE could rapidly expand the ventilation capacity of health care facilities during emergency situations such as pandemics.

Caprine Models of the Agonist-Antagonist Myoneural Interface Implemented at the Above- and Below-Knee Amputation Levels.

BACKGROUND: Traditional approaches to amputation are not capable of reproducing the dynamic muscle relationships that are essential for proprioceptive sensation and joint control. In this study, the authors present two caprine models of the agonist-antagonist myoneural interface (AMI), a surgical approach designed to improve bidirectional neural control of a bionic limb. The key advancement of the AMI is the surgical coaptation of natively innervated agonist-antagonist muscle pairs within the residual limb. METHODS: One AMI was surgically created in the hindlimb of each of two African Pygmy goats at the time of primary transtibial amputation. Each animal was also implanted with muscle electrodes and sonomicrometer crystals to enable measurement of muscle activation and muscle state, respectively. Coupled agonist-antagonist excursion in the agonist-antagonist myoneural interface muscles was measured longitudinally for each animal. Fibrosis in the residual limb was evaluated grossly in each animal as part of a planned terminal procedure. RESULTS: Electromyographic and muscle state measurements showed coupled agonist-antagonist motion within the AMI in the presence of both neural activation and artificial muscle stimulation. Gross observation of the residual limb during a planned terminal procedure revealed a thin fibrotic encapsulation of the AMI constructs, which was not sufficient to preclude coupled muscle excursion. CONCLUSIONS: These findings highlight the AMI's potential to provide coupled motion of distal agonist-antagonist muscle pairs preserved during below- or above-knee amputation at nearly human scale. Guided by these findings, it is the authors' expectation that further development of the AMI architecture will improve neural control of advanced limb prostheses through incorporation of physiologically relevant muscle-tendon proprioception.

Towards functional restoration for persons with limb amputation: A dual-stage implementation of regenerative agonist-antagonist myoneural interfaces.

While amputation has traditionally been viewed as a failure of therapy, recent developments in amputation surgery and neural interfacing demonstrate improved functionality and bidirectional communication with prosthetic devices. The agonist antagonist myoneural interface (AMI) is one such bi-directional neural communication model comprised of two muscles, an agonist and an antagonist, surgically connected in series within the amputated residuum such that contraction of one muscle stretches the other. By preserving agonist-antagonist muscle dynamics, the AMI allows proprioceptive signals from mechanoreceptors within both muscles to be communicated to the central nervous system. Preliminary human evidence suggests that AMIs have the capacity to provide high fidelity control of a prosthetic device, force feedback, and natural proprioception. However, AMIs have been implemented only in planned amputations and require healthy distal tissues, whereas the majority of amputations occur in patients who do not have healthy distal tissues. Through the use of a dual-stage surgical procedure which leverages existent tissues, this study proposes a revision model for implementation of the AMI in patients who are undergoing traumatic amputation or have already undergone a standard amputation. This paper validates the resulting AMI's physiology, revealing robust viability and mechanical and electrophysiological function. We demonstrate the presence of H-waves in regenerative grafts, indicating the incorporation of the AMI into physiological reflexive loops.